Process for producing carbapenem derivative and intermediate crystal therefor

ABSTRACT

An object of the present invention is to provide a carbapenem synthetic intermediate which is advantageous in an industrial process. There are provided a process for producing Compound (I), or a pharmaceutically acceptable salt, or a solvate, or a crystal thereof, comprising reacting Compound (III) and Compound (IV) in the presence of the secondary amine, and a benzyl alcoholated crystal of Compound (I). There are further provided a method of deprotecting Compound (I) with a Pd catalyst, and a crystal of Compound (IV).

TECHNICAL FIELD

The present invention relates to a process for producing a carbapenemderivative and an intermediate crystal therefor.

BACKGROUND TECHNIQUE

A pyrrolidylthiocarbapenem derivative (Compound (II)) having a broadrange of an antibacterial spectrum is known as a useful antibiotic (see:Patent Literature 1). Compound (I) of the present invention is asynthetic intermediate therefor.

(wherein R¹ is a carboxy protecting group: R² is an amino protectinggroup)

As an example of production of Compound (I), Patent Literature 1(Example 13, step 3) describes the following method, but a base used ata condensation reaction for introducing a 2-positional side chain isdiisopropylethylamine (yield 71%).

In addition, Patent Literature 2 (Reference Example 1) also describesthe following similar reaction, but a base used at a condensationreaction is the same diisopropylethylamine (yield 54%).

Further, a method of synthesizing a carbapenem derivative having apyrrolidinylthio group of another structure at a 2-position is known,but as a base at a condensation reaction at a 2-position,diisopropylethylamine is also used (see: Patent Literature 3, Examples1, 7 etc.).

Like this, as the base at a 2-positional condensation reaction ofcarbapenem, tertiary amine such as diisopropylethylamine and the like isgenerally used. The reason is presumed as follows: tertiary amine isgenerally strongly basic, and it is thought that a side reaction hardlyoccurs because there is not hydrogen on the N atom.

In addition, regarding crystallization of the Compound (I-a), variousalcoholated crystals (example: 2-propanol, 2-pentanol, 1-pentanol,t-amyl alcohol, 1-propanol) are known (see: Patent Literature 2).

In addition, the Compound (IV-a) which is a synthetic intermediate forCompound (I-a) is described in Patent Literature 1 (see: PreparationExample 8), but a crystal thereof is not isolated.

Further, as a method of deprotecting Compound (I-a), a Sn reagent (see:Patent Literature 1) and Meldrum's acid (see: Patent Literature 2) wereused, but from a viewpoint of loading on the environment and stabilityof a reagent itself, they were not preferable for industrialimplementation. On the other hand, as other reagent for deprotecting acarbapenem derivative, a combination of amine and a Pd catalyst is known(see: Patent Literature 4). In Patent Literature 4, amine is used as areceptor for a lower alkenyl group, and as preferable amine, there isexemplified aromatic amines such as aniline, N-methylaniline and thelike.

[Patent Literature 1]

-   Japanese Patent Application Laid-Open (JP-A) No. 05-294970

[Patent Literature 2]

-   WO/2004/72073

[Patent Literature 3]

-   JP-A No. 2-15080

[Patent Literature 4]

-   JP-A No. 64-79180

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Development of a further preferable industrial process for producingCompound (I) which is an intermediate of a carbapenem derivative isdesired. In addition, development of a further preferable crystal ofCompound (I) is desired. Further, development of an industriallypreferable method of deprotecting Compound (I), and a crystal ofCompound (IV-a) or the like which is an intermediate of Compound (I) isdesired.

Means to Solve the Problems

In view of the above problems, the present inventors intensivelycontinued to study and, as a result, found out that, when a particularbase, preferably secondary amine is used at a 2-positional condensationreaction of carbapenem, a reaction yield is improved, a reaction time isshortened, and Compound (I) can be effectively produced. In addition, itwas also found out that, when Compound (I) is crystallized from benzylalcohol or the like, a crystal which is excellent in handling as anintermediate is obtained. Further, a method of deprotecting Compound (I)in the presence of a Pd catalyst and particular amine, and a crystal ofCompound (IV-a) or the like were found out, resulting in completion ofthe following present invention.

-   (1) A process for producing Compound (I) represented by the formula:

-   (wherein R¹ and R² are as defined below),-   or a pharmaceutically acceptable salt thereof, or a solvate or a    crystal thereof, comprising:-   reacting Compound (III) represented by the formula:

-   (wherein R is hydrogen or a hydroxyl protecting group; R¹ is a    carboxy protecting group; Ph is phenyl)-   with Compound (IV) represented by the formula:

-   (wherein R² is an amino protecting group),-   or a pharmaceutically acceptable salt thereof in the presence of    secondary amine and, optionally, deprotecting the hydroxyl    protecting group.-   (2) The process according to (1), wherein the secondary amine is    diisopropylamine.-   (3) The process according to (1) or (2), wherein R¹ is CH₂CH═CH₂; R²    is COOCH₂CH═CH₂.-   (4) A process for producing Compound (II) represented by the    formula:

-   or a pharmaceutically acceptable salt thereof, or a solvate thereof,    comprising:-   obtaining Compound (I), or a pharmaceutically acceptable salt    thereof, or a solvate or a crystal thereof by a method as defined in    any one of (1) to (3), and subjecting this to a deprotecting    reaction.-   (5) A solvated crystal (provided that the solvent is optionally    substituted benzyl alcohol) of Compound (I-a) represented by the    formula:

-   (6) The crystal according to (5), which is a benzyl alcoholated    crystal.-   (7) The crystal according to (3), wherein a content of benzyl    alcohol is 1 to 10 mole equivalent relative to Compound (I).-   (8) The crystal according to (6) or (7), wherein a main peak is    present at a diffraction angle 2θ=around 7.6, 17.7, 18.5, 19.5,    19.9, 21.3, 23.8 (unit: degree) in a powder X-ray diffraction    pattern.-   (9) A process for producing Compound (II) represented by the    formula:

-   or a pharmaceutically acceptable salt thereof, or a solvate thereof,    comprising:-   deprotecting a crystal as defined in any one of (5) to (8).-   (10) The process for producing Compound (II), or a pharmaceutically    acceptable salt thereof, or a solvate thereof according to (9),    comprising obtaining Compound (I), or a pharmaceutically acceptable    salt thereof, or a solvate thereof by the method as defined in any    one of (1) to (3), crystallizing this in optionally substituted    benzyl alcohol to obtain an optionally substituted benzyl    alcoholated crystal of Compound (I), and deprotecting this.-   (11) A process for producing Compound (II) represented by the    formula:

-   or a pharmaceutically acceptable salt thereof, or a solvate thereof,    comprising:-   deprotecting a compound represented by the formula:

-   (wherein R¹ is a carboxy protecting group; R² is an amino protecting    group),-   or a solvate thereof or a crystal thereof in the presence of a Pd    catalyst and N-ethylaniline.-   (12) The process according to (11), wherein R¹ is CH₂CH═CH₂; R² is    COOCH₂CH═CH₂.-   (13) The process according to (11), wherein an amount of the Pd    catalyst to be used is 0.01 mole equivalent or less relative to    Compound (I).-   (14) The process according to (11), wherein an amount of the Pd    catalyst to be used is 0.005 mole equivalent or less relative to    Compound (I).-   (15) A crystal of a compound represented by the formula:

-   (16) The crystal according to (15), wherein a main peak is present    at a diffraction angle 2θ=around 6.26, 12.50, 18.24, 18.80, 23.90,    and 26.86 (unit: degree) in a powder X-ray diffraction pattern.-   (17) A crystal of a compound represented by the formula:

-   (wherein Ac is acetyl; Boc is t-butoxycarbonyl).-   (18) The crystal according to (17), wherein a main peak is present    at a diffraction angle 2θ=around 10.24, 12.26, 13.34, 17.32, 20.84,    21.22, 21.72 and 22.28 (unit: degree) in a powder X-ray diffraction    pattern.

Effect of the Invention

According to the present process, Compound (I) can be produced at abetter yield and in a short time. In addition, a solvated crystal ofCompound (I) which is excellent in handling is obtained. In addition, amethod of deprotecting Compound (I) in the presence of a Pd catalyst,and a crystal of an intermediate are provided. By utilizing theseprocesses, and crystals, Compound (II) which is a carbapenemantibacterial agent, or a solvate thereof, or a crystal thereof can beeffectively produced.

BEST MODE FOR CARRYING OUT THE INVENTION (1) Production of Compound (I)

(wherein R is hydrogen or a hydroxy protecting group; R¹ is a carboxyprotecting group; R² is an amino protecting group, and Ph is phenyl)

By reacting Compound (III) with Compound (IV) or a pharmaceuticallyacceptable salt thereof in the presence of a base and, optionally,deprotecting the hydroxy protecting group, Compound (I), or apharmaceutically acceptable salt thereof, or a solvate thereof or acrystal thereof is obtained.

As the base, secondary amine is used, and more preferable is secondaryamine having relatively great steric hindrance. Specifically, it isrepresented by NHR^(a)R^(b), wherein R^(a) and R^(b) are independentlyalkyl, phenyl or the like, preferably R^(a) and R^(b) are the same. Thealkyl is straight or branched C1-C10, preferably C3-C7alkyl, morepreferably is branched. As R^(a) and R^(b), isopropyl, t-butyl,isobutyl, amyl and phenyl are further preferably exemplified. Assecondary amine, more preferable are diisopropylamine, di-t-butylamine,diisobutylamine, diamylamine, and diphenylamine, particularly preferableis dialkylamine (e.g.: diisopropylamine).

Examples of a reaction solvent include acetonitrile, dimethylformamide,methylene chloride, dimethyl sulfoxide, N-dimethylacetamide and thelike, preferably N-dimethylacetamide.

A reaction temperature is usually −40° C. to room temperature,preferable about −20 to 0° C.

A reaction time is usually a few tens minutes to a few tens hours,preferably 1 to 5 hours.

Compound (III) and Compound (IV) are used at an amount of 10:1 to 1:10,preferably 1:1 to 1:5.

Examples of the pharmaceutically acceptable salt include inorganic basesalts (e.g.: alkali metal salts such as sodium salt, potassium saltetc.; alkaline earth metal salts such as calcium salt, magnesium saltetc.; ammonium salt); organic base salts (e.g.: triethylamine salt,pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt); inorganicacid addition salts such as hydrochloride, hydrobromide, sulfate,phosphate etc.; organic acid addition salts such as formate, acetate,trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonateetc.; salts with basic amino acids or acidic amino acids such asarginine, aspartic acid, glutamic acid etc.

As the hydroxy protecting group represented by R, various hydroxylprotecting groups which can be generally used in the field of β-lactamantibacterial agents can be used. Specific examples includetrialkylsilyl (the alkyl is preferably C1-C6, e.g.: trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl,dimethylhexylsilyl, t-butyldiphenylsilyl), optionally substituted benzyl(example of substituent: nitro, lower alkoxy), lower alkoxycarbonylgroup (e.g.: methoxycarbonyl, ethoxycarbonyl), halogeno loweralkoxycarbonyl group, optionally substituted benzyloxycarbonyl (exampleof substituent: nitro, lower alkoxy), acyl (e.g.: acetyl, benzoyl),aralkyl (e.g.: triphenylmethyl), tetrahydropyranyl and the like.Preferable is trialkylsilyl, particularly preferable is trimethylsilyland t-butyldimethylsilyl.

These hydroxy protecting groups can be optionally deprotected by methodswell-known to a person skilled in the art after a reaction.Alternatively, those protecting groups may be protecting groups whichare automatically eliminated during a coupling reaction or at apost-treatment (e.g.: extraction, washing) step. For example,trimethylsilyl or the like is eliminated with an acid in an extractionprocedure after a reaction.

Examples of the carboxy protecting group represented by R¹ include loweralkyl (e.g.: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl), lower alkanoyloxy (lower)alkyl (e.g.:acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,pivaloyloxymethyl, hexanoyloxymethyl), lower alkanesulfonyloxy(lower)alkyl (e.g.: 2-mesylethyl), mono (or di or tri) halo (lower)alkyl(e.g.: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy(lower)alkyl (e.g.: methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonyloxymethyl, tertiary butoxycarbonyloxymethyl, 1- (or2-)methoxycarbonyloxyethyl, 1- (or 2-)ethoxycarbonyloxyethyl, 1- (or2-)isopropoxycarbonyloxyethyl), lower alkenyl (e.g.: vinyl, allyl),lower alkynyl (e.g.: ethynyl, propynyl), (substituted) aryl (lower)alkyl(e.g.: benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl,benzhydryl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl,4-hydroxy-3,5-di-tertiary butylbenzyl), (substituted) aryl (e.g.:phenyl, 4-chlorophenyl, tolyl, tertiary butylphenyl, xylyl). Among them,R¹ is preferably lower alkyl, lower alkenyl (e.g.: vinyl, allyl), loweralkynyl, (substituted) aryl(lower)alkyl, or (substituted) aryl sincethere is a great advantage of utilization of the present process in thecase of a relatively electron donating protecting group. Furtherpreferable is a protecting group which is hardly eliminated during acoupling reaction, and particularly preferable is allyl (—CH₂CH═CH₂).

Examples of the amino protecting group represented by R² includealiphatic acyl groups derived from carboxylic acid, carbonic acid,sulfonic acid and carbamic acid, and aliphatic acyl groups substitutedwith an aromatic group.

Examples of the aliphatic acyl group include saturated or unsaturatedalicyclic or cyclic acyl groups, for example, alkanoyl groups such aslower alkanoyl groups such as formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like,alkylsulfonyl groups such as lower alkylsulfonyl groups such as mesyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like, carbamoylgroups, for example, N-alkylcarbamoyl groups such as methylcarbamoyl,ethylcarbamoyl and the like, alkoxycarbonyl groups such as loweralkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like,alkenyloxycarbonyl groups such as lower alkenyloxycarbonyl groups suchas vinyloxycarbonyl, allyloxycarbonyl and the like, alkenoyl groups suchas lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl andthe like, and cycloalkanecarbonyl groups such ascyclo(lower)alkanecarbonyl groups such as cyclopropanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl and the like.

Examples of the aliphatic acyl group substituted with an aromatic groupinclude aralkoxycabonyl groups such as phenyl(lower)alkoxycarbonylgroups such as benzyloxycarbonyl, phenethyloxycarbonyl and the like.

These acyl groups may be further substituted with one or more suitablesubstituents such as a nitro group, and examples of such the preferableacyl group having a substituent include nitroaralkoxycarbonyl groupssuch as nitrobenzyloxycarbonyl and the like.

The amino protecting group is preferably a protecting group which ishardly eliminated during a coupling reaction, particularly preferably analkenyloxycarbonyl group (e.g.: —COOCH₂CH═CH₂).

(2) Crystal of Compound (I-a)

Compound (I-a) can be crystallized from an alcohol solvent. The alcoholis preferably optionally substituted benzyl alcohol, and the alcoholatedcrystal is obtained. Examples of a substituent of optionally substitutedbenzyl alcohol include lower alkyl, preferably C1-C4 alkyl (e.g.:methyl, ethyl, propyl), lower alkoxy (e.g.: methoxy, ethoxy, propoxy),halogen (e.g.: F, Cl, Br), optionally substituted amino (example ofsubstituent: lower alkyl), nitro, cyano, OH and the like, and asubstitution position may be any of ortho, meta and para.

The optionally substituted benzyl alcoholated crystal is preferably abenzyl alcoholated crystal. A content of benzyl alcohol in the benzylalcoholated crystal is 0.1 to 5 mole equivalent, preferably 0.5 to 2mole equivalent, more preferably 1 mole equivalent relative to Compound(I-a). The benzyl alcoholated crystal preferably exhibits a pattern ofFIG. 1 in powder X-ray diffraction.

The benzyl alcoholated crystal preferably has a main peak around on atleast following positions indicated below in a powder X-ray diffractionpattern. 2θ=7.6, 17.7, 18.5, 19.5, 19.9, 21.3, 23.8 (unit: degree)(X-ray diffraction measuring condition: tubular lamp CuKα ray, tubularvoltage 30 Kv, tubular current 15 mA, d sin θ=nλ (n is integer, θ isdiffraction angle))

The aforementioned spacing d value is such that, among X-ray peaks, mainpeaks having a strong relative intensity are selected, but a crystalstructure is not particularly limited only by these values. That is,peaks other than these peaks may be contained. In addition, generally,when a crystal is measured by X-ray analysis, peaks may generate aslight measurement error, depending on a measuring instrument, measuringcondition, the presence of an attached solvent or the like. For example,a measurement error of around ±0.2 as expressed by a value of spacing dmay be generated in some cases and, even when a very precise facility isused, a measurement error of around ±0.01 to ±0.1 may be generated insome cases. Therefore, upon identification of a crystal structure,slight error may be taken into consideration, and all of crystals whichare characterized by substantially the same X-ray pattern as thatdescribed above are within the scope of the present invention.

When the benzyl alcoholated crystal is prepared from Compound (I-a),preferably, the compound is obtained by dissolving Compound (I-a) or asolvate thereof in a soluble solvent, adding benzyl alcohol, stirringthis at room temperature for a few hours and, optionally allowing tostand this at 0° C. to room temperature for a few hours to a few days,followed by filtering and drying according to a conventional method.Alternatively, after Compound (I-a) or a solvate thereof is dissolved ina large amount of a solvent, a solvent is once distilled off to obtain aconcentrate, to this are added benzyl alcohol and, optionally, otherorganic solvent, and stirring, filtration, drying and the like may beperformed as described above.

As the solvent, following soluble solvents, insoluble solvents and amixture thereof are exemplified.

As the soluble solvent, alcohols such as methanol, ethanol, ethyleneglycol, methoxyethanol, glycerin, and propylene glycol, ethers such asdioxane, tetrahydrofuran, and dimethoxyethane, ketones such as acetone,methyl ethyl ketone, and methyl isobutyl ketone, esters such as methylformate, ethyl formate, propyl formate, methyl acetate, ethyl acetate,propyl acetate, butyl acetate, methyl propionate, and ethyl propionate,organic halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane, trichloroethane,chlorobenzene, dichlorobenzene, nitriles such as acetonitrile, andpropionitrile, dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, quinoline, pyridines, and triethylamine can beused. These solvents may be used alone, or two or more kinds may be usedby mixing them. Alternatively, they may be used by mixing with water.Preferable is ethyl acetate.

As the insoluble solvent, alcohols such as 2-propanol, 2-pentanol,1-pentanol, t-amyl alcohol, 1-propanol, n-propanol, t-propanol,isobutanol, n-butanol, cyclohexanol, and benzyl alcohol, ethers such asdiethyl ether, isopropyl ether, dibutyl ether, ethyl isoamyl ether, andethyl phenyl ether, and hydrocarbons such as n-pentane, n-hexane,n-heptane, n-octane, n-decane, cyclohexane, methylcyclohexane, toluene,benzene, ethylbenzene, cumene, cymene, and xylene can be used. Thesesolvents may be used alone, or two or more kinds may be used by mixingthem.

A ratio of the soluble solvent and the insoluble solvent to be used isusually 1:0 to 1:1000, preferably 1:0.1 to 1:100, particularlypreferably 1:1 to 1:50, or usually 0:1 to 1000:1, preferably 0.1:1 to100:1, particularly preferably 1:1 to 50:1 by weight. Preferably, ethylacetate and benzyl alcohol are used at a ratio of 1:1 to 5.

A benzyl alcoholated crystal of Compound (I-a) has excellentcrystallizability as apparent from its clear X-ray peaks. Therefore,when Compound (I-a) is synthesized by a 2-positional condensationreaction, and is isolated as a benzyl alcoholated crystal, an objectivesubstance is obtained at a better yield and a high purity. In addition,handling property is better, and storage stability is high. Therefore,this is very useful as a synthetic intermediate for Compound (II) whichis a carbapenem antibacterial agent. Alternatively, when Compound (I-a)is isolated as a benzyl alcoholated crystal from a reaction solutionafter a 2-positional condensation reaction, preferably, the compound maybe crystallized by washing the reaction extract, distilling a solventoff, drying this, dissolving the material in a soluble solvent asdescribed above, and adding benzyl alcohol and, optionally, otherinsoluble solvent. Alternatively, in adding benzyl alcohol, optionally,a separately prepared benzyl alcoholated crystal of Compound (I-a) maybe added as a seed crystal.

(3) Step of Deprotecting Compound (I), or a Solvate or a Crystal thereof

By subjecting Compound (I), a pharmaceutically acceptable salt thereof,or a solvate or a crystal thereof, preferably a benzyl alcoholatedcrystal of Compound (I-a) to a deprotecting reaction, Compound (II)which is an antibacterial agent disclosed in JP-A No. 05-294970, or apharmaceutically acceptably salt, or a solvate thereof, or a crystalthereof is obtained.

The deprotecting reaction is performed according to the methodwell-known to a person skilled in the art. In the present reaction, anickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalystand a noble metal catalyst such as a platinum catalyst and a palladiumcatalyst are used. Preferably, the palladium catalyst and the nickelcatalyst are used, and more preferably,tetrakis(triphenylphosphine)palladium, (triphenylphosphine)palladiumacetate and (triethylphosphite)palladium acetate are used. An additive(preferably triphenylphosphine etc.) may be added to a mixed solution towhich palladium has been added. Further preferably, a reducing agent forreduction-removing a protecting group or a nucleophile (trapping agentfor aryl group) is added to the palladium catalyst. The reducing agentis hydrogen, metal hydride or the like, preferably tri-n-butyltinhydride or the like. Examples of the nucleophile include carboxylate(e.g. sodium 2-ethylhexanoate etc.), 1,3-dicarbonyl compound (e.g.Meldrum's acid, dimedone and malonic acid ester etc.), secondary amine(e.g. diethylamine etc.), and aromatic amine.

When the environmental aspect and a reaction yield are taken intoconsideration, a deprotecting reagent is more preferably a combinationof a palladium catalyst (e.g.: tetrakis(triphenylphosphine)palladium)and aromatic amine (e.g.: aniline derivative). Examples of the anilinederivative include aniline, N-methylaniline, N-ethylaniline,N,N-dimethylaniline, and electron donating group-substituted anilinessuch as o-, m- or p-toluidine, o-, m- or p-anisidine and the like,particularly preferably N-ethylaniline. By using N-ethylaniline, evenwhen an amount of the Pd reagent to be used is considerably reduced(e.g.: not more than 0.01 mole equivalent, preferably not more than0.005 mole equivalent, more preferably 0.003 to 0.001 mole equivalentrelative to Compound (I)), a deprotecting reaction proceeds at a highyield. In addition, a production rate of byproduct which is derived froma protecting group and aniline reagent is low and, further, handlingprocedure of Compound (II) precipitated after deprotection is better,being suitable as a large scale production method.

An amount of aromatic amine (e.g.: aniline derivative) to be used is 1to 20 mole equivalent, preferably 5 to 15 mole equivalent relative toCompound (I).

As a solvent used in the deprotecting reaction, any solvent may be usedas far as it is used in a normal reaction. Preferable are acetone,acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, methanol,ethanol and water. These solvents may be used alone, or two or morekinds may be used by mixing them. Particularly preferable is acombination of tetrahydrofuran and water, and the combination ispreferably used at a ratio of tetrahydrofuran:water=1:1 to 10:1.

Compound (I), or a pharmaceutically acceptable salt thereof, or asolvate or a crystal thereof, and a nucleophile are added to a solvent,and a reaction system (e.g. a reaction mixed solution and a vessel) ispreferably filled with nitrogen.

A reaction temperature is in a range of about −20 to 50° C., preferably0 to 30° C.

A reaction time is usually a few minutes to a few tens hours, preferablyin a range of 1 to 3 hours.

The present invention further provides each crystal of Compound (IV-a)and (V-a) which are a synthetic intermediate for Compound (I-a).

(Ac=acetyl; Boc=t-butoxycarbonyl)

(1) Crystal of Compound (IV-a)

The present crystal has main peaks around diffraction angle 2θ=at least6.26, 12.50, 18.24, 18.80, 23.90, and 26.86 (unit: degree) in a powderX-ray diffraction pattern. More particularly, a pattern in FIG. 3 isshown. A crystal of Compound (IV-a) may be a solvate (e.g.: hydrate,alcoholate).

(2) Crystal of Compound (V-a)

The present crystal has main peaks around diffraction angle 2θ=at least10.24, 12.26, 13.34, 17.32, 20.84, 21.22, 21.72 and 22.28 (unit: degree)in a powder X-ray diffraction pattern. More particularly, a pattern inFIG. 4 is shown. A crystal of Compound (V-a) may be a solvate (e.g.:hydrate, alcoholate).

A crystal of Compound (IV-a), as shown in Example later, can becrystallized with an organic solvent (preferably ethyl acetate-toluenesystem) after a crystal of Compound (V-a) is deprotected with preferablyan acid, more preferably an inorganic acid (e.g.: hydrochloric acid), apH of the reaction is adjusted with an alkali (preferably pH 2 to 3) toprecipitate the compound, and dried and concentrated by a conventionalmethod. Alternatively, after Compound (VI-a) is reacted with H₂NSO₂NHBocto produce Compound (V-a), this may be subsequently subjected to adeprotecting reaction without isolation as described above. When thereis a possibility that a byproduct derived from an amino-protecting groupis generated at a deprotecting reaction, preferably, a radical trappingagent may be used jointly. Examples of the radical trapping agentinclude dibutylhydroxytoluene.

In the present process, by using the above-obtained Compound (I), apharmaceutically acceptable salt, a solvate thereof or a crystalthereof, having a high purity, it has become possible to prepare anaqueous solution in which an objective Compound (II) is dissolved at ahigh concentration, in an impurity extraction procedure using water andan organic solvent, preferably dichlohomethane after a deprotectingreaction. As a result, concentration and column chromatography treatmentwhich have previously been essential in a post-treatment step become notan essential procedure, and it has become possible to easily isolate anobjective pyrrolidylthiocarbapenem derivative (II), or apharmaceutically acceptable salt, or a solvate or a crystal thereof.Therefore, the present process is useful also as an industrial process.

Examples will be shown below.

EXAMPLE 1

2-Propanolated crystal (3.340 g, corresponding to 3.137 g in terms ofnon-solvent) of Compound (I-a) described in WO 2004/72073 was dissolvedin ethyl acetate (67 ml), and ethyl acetate and isopropanol weredistilled off to obtain an ethyl acetate concentrate (4.551 g). To thiswere added ethyl acetate (3.14 ml), benzyl alcohol (3.14 ml), andtoluene (12.55 ml), and the mixture was stirred at room temperature for2 hours, and at 5° C. for 1 hour. The precipitated crystal was filtered,washed with toluene (6.26 ml), and air-dried to obtain a benzylalcoholated crystal of Compound (I-a) (3.668 g, corresponding to 3.037 gin terms of non-solvent, containing benzyl alcohol (1.0 mol)). Yield:96.8%

Mp. 74.9° C.

Elementary Analysis for C₂₂H₃₁N₄O₈S₂.1.0C₇H₈O.0.2H₂O

Calcd: C: 53.15; H: 6.06; N: 8.55; S: 9.79. Found: C: 53.19; H: 6.12; N:8.65; S: 9.85.

Powder X-ray diffraction: a chart is shown in FIG. 1 and peak values areshown in FIG. 2.

Regarding other alcohol solvate crystals of Compound (I-a) (solventexample: 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol,1-propanol), when stored under the general environment of 25° C. and 1atom, phenomenon was recognized, in which the crystal was efflorescedwith time, and an amount of a contained solvent was reduced. However,regarding a benzyl alcoholated crystal, such the phenomenon was notrecognized in handling for a few days, and it was seen that the crystalhas high stability.

EXAMPLE 2

Amorphous powdery Compound (I-a) (100 mg) was dissolved in ethyl acetate(0.1 ml), benzyl alcohol (0.3 ml) was added, and the mixture was stirredat room temperature for 1 hour, and allowed to stand at 5° C. for 2days. A precipitated crystal was filtered, and air-dried to obtain abenzyl alcoholated crystal of Compound (I-a) (79 mg) exhibitingsubstantially the same powder X-ray pattern as that of Example 1.

EXAMPLE 3

(wherein Me=methyl; Ph=phenyl)

Diisopropylamine (0.168 ml; 1.2 mmol) was added dropwise to a solutionof 595 mg (1 mmol) of enolphosphate (III-a) in which hydroxy on a6-positional side chain was protected, and 345 mg (1.1 mmol) of thiol(IV-a) in 2 ml of N-dimethylacetamide at −12 to −8° C., and the mixturewas stirred at the same temperature for 1 hour and 30 minutes. At thistime point, it was confirmed by HPLC that a condensation reactionproceeded 92%. The reaction solution was poured into dilute hydrochloricacid, followed by extraction with ethyl acetate. The organic layer wassequentially washed with water, a 5% aqueous sodium bicarbonatesolution, and water, and dried with sodium sulfate, and a solvent wasdistilled off. The residue was dissolved in 2 ml of ethyl acetate, 0.5ml of benzyl alcohol, and a crystal obtained in Example 2 as a seedcrystal were added, and the mixture was stirred at room temperature for2 hours. Toluene (5 ml) was slowly added, and the mixture was furtherstirred at room temperature for 2 hours, and cooled to 5° C. Afterfiltration and drying, 554 mg (85%) of a benzyl alcoholated crystal ofCompound (I-a) exhibiting substantially the same powder X-ray pattern asthat of Example 1 was obtained.

EXAMPLE 4

Diisopropylamine (0.168 ml; 1.2 mmol) was added dropwise to a solutionof 500 mg (1 mmol) of enolphosphate (III-b) and 345 mg (1.1 mmol) ofthiol (IV-a) in 2 ml of N-dimethylacetamide at −15° C., and the mixturewas stirred at the same temperature for 3 hours. At this time point,production of Compound (I-a) was confirmed (HPLC quantitation: 92%). Thereaction solution was poured into dilute hydrochloric acid, followed byextraction with ethyl acetate. The organic layer was sequentially washedwith water, a 5% aqueous sodium bicarbonate solution, and water, anddried with sodium sulfate, and a solvent was distilled off. The residuewas diluted in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol and acrystal obtained in Example 2 as a seed crystal were added, and themixture was stirred at room temperature for 2 hours. Toluene (5 ml) wasslowly added, and the mixture was further stirred at room temperaturefor 2 hours, and cooled to 5° C. After filtration and drying, 548 mg(84%) of a benzyl alcoholated crystal of Compound (I-a) exhibitingsubstantially the same powder X-ray pattern as that of Example 1 wasobtained.

EXAMPLE 5

A benzyl alcoholated crystal (2.0 g; 3.06 mmol) of Compound (I-a) wasdissolved in 12 ml of tetrahydrofuran, 1 ml of isopropanol, 3.71 ml(30.62 mmol) of N-ethylaniline, 4 ml of water, and 7.1 mg (0.2 eq) of Pd(PPh₃)₄ (Ph=phenyl) were sequentially added, and the mixture was stirredat 25° C. for 3 hours under a nitrogen stream. Then, after allowing tostand at the same temperature for 1.5 hours, and at 5° C. for 16 hours,a precipitate was filtered and dried to obtain 1.26 g (94%) of anobjective material (11).

EXAMPLE 6

The similar reaction to that of Example 5 was performed by reducing anamount of the Pd catalyst to be used.

Compound (I-a) (provided that an isopropyl alcoholated crystal was used)(500 mg) was dissolved in 2 ml of tetrahydrofuran (THF), 10 equivalentof N-ethylaniline, 2 ml of THF, and 1 ml of H₂O were sequentially added,and degassing under reduced pressure and nitrogen replacement of acharging solution were repeated three times. Further, 0.002 equivalentof Pd(PPh₃)₄ and 2 ml of THF were sequentially added, and degassingunder reduced pressure and nitrogen replacement of a charging solutionwere further repeated three times. Under the condition of roomtemperature, nitrogen atmosphere and stirring with a stirrer, a reactionwas performed for about 1.5 hours, and Compound (II) was initiated to becrystallized. Disappearance of raw materials, and a reactionintermediate was confirmed by HPLC, thereafter, three hours afterinitiation of a reaction, dimethylformamide (DMF) was added touniformize the reaction solution. A generation rate of Compound (II)calculated from this reaction solution was 92%.

COMPARATIVE EXAMPLE 1

The reaction of Example 6 was performed using N-methylaniline in placeof N-ethylaniline, and a generation rate of Compound (II) was found tobe 89%. In addition, a nature of precipitated Compound (II) was viscousas compared with the case of use of N-ethylaniline, and was partiallymassy, and a part of the compound was adhered to a wall of a reactionvessel.

Further, the similar reaction was performed using other electrondonating group-substituted anilines (e.g.: N,N-dimethylaniline,toluidine, anisidine) in place of N-ethylaniline, and a generation rateof Compound (II) was lower (yield 0 to 86%) in any case as compared withthe case of use of N-ethylaniline.

COMPARATIVE EXAMPLE 2

The reaction of Example 6 was performed similarly using aniline in placeof N-ethylaniline (provided that, as a solvent, THF (12V) -water (2V)was used). As shown below, when an amount of the Pd catalyst to be usedwas reduced, a large amount of a byproduct was generated, and ageneration rate of Compound (II) was remarkably reduced.

TABLE 1 Reaction Generation rate Pd(PPh₃)₄ time of Compound (II) (eq)(h) (%) 0.0200 0.5 86 0.0100 0.5 84 0.0050 1.5 83 0.0025 5.0 70

EXAMPLE 7

(1) Synthesis of 7 (Crystal of Compound (V-a))

DIAD (diethyl azodicarboxylate) (23.63 g; 1.2 eq) was added dropwise toa solution containing 26.7 g (0.1 mol, 97.1% purity) of Compound 6synthesized by the method described in JPA (Kokai) No. 5-294970 or theabove route, 26.49 g (1.35 eq) of H₂NSO₂NHBoc (Boc=t-butoxycarbonyl),and 32 g (1.22 eq) of PPh₃ (triphenylphosphine) in 400 ml of ethylacetate at room temperature for 30 minutes. After stirred at the sametemperature for 16 hours, ethyl acetate was distilled off under reducedpressure, and the solvent was replaced with 100 ml of toluene. Aprecipitated reduced entity of DIAD was filtered, and concentrated underreduced pressure. The residue was subjected to silica gelchromatography, and an elution portion at n-hexane-ethyl acetate=2:1 wasconcentrated to obtain 48.5 g of an objective substance 7.Crystallization from ethyl ether afforded 27.12 g (62%) of a crystal.

Mp. 115° C.

Anal for C₁₆H₂₇N₃O₇S₂ (FW 437.53), Calcd.; C, 43.92; H, 6.22; N, 9.60;S, 14.66. Found; C, 43.87; H, 6.20; N, 9.67; S, 14.37.

¹H NMR (CDCl₃): δ 1.51 (s, 9H), 2.34 (s, 3H), 2.53-2.63 (m, 1H),3.19-3.25 (m, 1H), 3.57-3.63 (m, 1H), 3.90-4.04 (m, 2H), 4.20-4.27 (m,3H), 4.52-4.54 (m, 3H), 5.21-5.32 (m, 3H), 5.82-5.96 (m, 4H)

λ_(max) ^(MeOH) ε(nm); 4,310 (231)

ν_(max) ^(Nujol) 3374, 3195, 1721, 1678 cm⁻¹

[α]₃₆₅ ^(22°)+4.6±0.5°, [α]₄₃₆ ^(22°)+1.2±0.4° (MeOH, C=1.00%)

Powder X-ray diffraction data is shown in FIG. 4. A peak of peak No. 23is a peak derived from aluminum used at measurement.

(2) Synthesis of 8 from 6 (Crystal of Compound (VI-a))

DIAD (22.80 g; 1.2 eq) was added dropwise to a solution of 26.48 g (0.1mol, 94% purity) of Compound 6, 24.89 g (1.35 eq) of H₂NSO₂NHBoc, and29.57 g (1.2 eq) of PPh₃ in 244 ml of ethyl acetate at room temperaturefor 30 minute. After stirred at the same temperature for 16 hours, ethylacetate was distilled off under reduced pressure, and the residue wasdissolved in 260 ml of methanol. Methanesulfonic acid (3.8 ml; 1.0 eq)was added, and the mixture was stirred at 65 to 70° C. for 4 hours.After cooling, a solvent was distilled off, and the residue was added to260 ml (2.2 eq) of a 0.5N NaOH solution, and washed with 260 ml of ethylacetate two times. Each ethyl acetate layer was back-extracted with 234ml (2 eq) of a 0.5N NaOH solution. The aqueous layers were combined,made acidic with hydrochloric acid, and extracted with 260 ml of ethylacetate two times. The extracts were washed with 130 ml of water,combined, and dried with Na₂SO₄, and a solvent was concentrated underreduced pressure to obtain 6.61 g (66.1%) of a crystal of 8.

When hydrochloric acid or hydrochloric acid/methanol solution was usedin place of methanesulfonic acid, the similar result was obtained.

Mp. 107-109° C.

Anal for C₉H₁₇N₃O₄S₂ (FW 295.38), Calcd.; C, 36.60;H, 5.80; N, 14.23; S,21.71. Found; C, 36.58; H, 5.75l N, 14.14l S, 21.82.

¹H NMR (CDCl₃) δ 1.72-1.74 (m, 2H), 2.55-2.64 (m, 1H), 3.11-3.22 (m,1H), 3.24-3.35 (m, 2H), 3.41-3.49 (m, 1H), 4.02-4.09 (m, 2H), 4.58-4.60(m, 2H), 4.71 (3, 2H), 5.24-5.35 (m, 2H), 5.87-6.00 (m, 2H)

[α]_(D) ^(23°)−49.7±0.9° (MeOH, C=1.004%)

Powder X-ray diffraction data is shown in FIG. 3. A peak of peak No. 20is a peak derived from aluminum used at measurement.

(3) Synthesis of 8 from 7

A 2.26N HCl/methanol solution (30.34 ml; 4 eq) was added to a solutionof 7.5 g (17.14 mol) of a crystal 7 in 15 ml of methanol at roomtemperature, and the mixture was stirred at 40° C. for 4.5 hours. Aftercooling, salting out was performed by adjusting a pH at 2.5 with a 10%NaOH aqueous solution, followed by extraction with 50 ml of ethylacetate three times. Each ethyl acetate layer was washed with 38 ml of a6% aqueous sodium chloride solution three times. Ethyl acetate layerswere combined, and dried with Na₂SO₄, a solvent was concentrated, andthis was crystallized from ethyl acetate-toluene system to obtain 8 4.77g (94.2%).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart of a powder X-ray diffraction pattern of a benzylalcoholated crystal of Compound (I-a) obtained in Example 1.

FIG. 2 shows peak values of a powder X-ray diffraction pattern of abenzyl alcoholated crystal of Compound (I-a) obtained in Example 1.

FIG. 3 is a chart of a powder X-ray diffraction pattern of a crystal ofCompound (IV-a) obtained in Example 7.

FIG. 4 is a chart of a powder X-ray diffraction pattern of a crystal ofCompound (V-a) obtained in Example 7.

1. A process for producing Compound (I) represented by the formula:

(wherein R¹ and R² are as defined below), or a pharmaceuticallyacceptable salt thereof, or a solvate or a crystal thereof, comprising:reacting Compound (III) represented by the formula:

(wherein R is hydrogen or a hydroxyl protecting group; R¹ is a carboxyprotecting group; Ph is phenyl) with Compound (IV) represented by theformula:

(wherein R² is an amino protecting group), or a pharmaceuticallyacceptable salt thereof in the presence of secondary amine and,optionally, deprotecting the hydroxyl protecting group.
 2. The processaccording to claim 1, wherein the secondary amine is diisopropylamine.3. The process according to claim 1, wherein R¹ is CH₂CH═CH₂; R² isCOOCH₂CH═CH₂. 4-18. (canceled)
 19. The process according to claim 2,wherein R¹ is CH₂CH═CH₂; R² is COOCH₂CH═CH₂.